Water Molecules Confined in Cryptophane Nanocages: Structures and Dynamics Driven by Hydrogen Bonding and Water Chains.

Cryptophanes (Crs) are roughly spherical organic nanocages used as vehicles for hosting xenon atoms in 129Xe NMR biosensor (XBS) structures. Crs also bind other guests, importantly water, which is abundant in biological systems. In other host cages, it has been found that the release of "high-energy" water from confinement constitutes an important contribution to the binding affinity of nonwater guests. Despite that, the role of water has received little attention in the XBS field. Based on molecular dynamics simulations in explicit water solvent, we here study the properties of confined water in three different CrA cages that have an identical interior but are functionalized with 0, 3, or 6 water solubility-enhancing, hydrophilic CH2COOH moieties. The number of the solubility groups is found to be a decisive factor for the structures and dynamics of the confined water. Formation of stable water-molecule chains is predicted within the cage with six hydrophilic groups, starting with the anchoring of one water molecule at the portal between the cage and the bulk solution. We find that the experimentally measured differences in the Xe-binding affinities of the cages can be related to the average number of hydrogen bonds per confined water molecule. The rotational dynamics of the confined water is significantly slower than that in the bulk, suggesting NMR relaxation measurements to study the intracavity water. The present findings reveal new details about the microscopic cryptophane-H2O host-guest chemistry, which will become important in the design of improved XBS devices.

NMR chemical shift of confined 129Xe: coordination number, paramagnetic channels and molecular dynamics in a cryptophane-A biosensor.

Advances in hyperpolarisation and indirect detection have enabled the development of xenon nuclear magnetic resonance (NMR) biosensors (XBSs) for molecule-selective sensing in down to picomolar concentration. Cryptophanes (Crs) are popular cages for hosting the Xe "spy". Understanding the microscopic host-guest chemistry has remained a challenge in the XBS field. While early NMR computations of XBSs did not consider the important effects of host dynamics and explicit solvent, here we model the motionally averaged, relativistic NMR chemical shift (CS) of free Xe, Xe in a prototypic CrA cage and Xe in a water-soluble CrA derivative, each in an explicit H2O solvent, over system configurations generated at three different levels of molecular dynamics (MD) simulations. We confirm the "contact-type" character of the Xe CS, arising from the increased availability of paramagnetic channels, magnetic couplings between occupied and virtual orbitals through the short-ranged orbital hyperfine operator, when neighbouring atoms are in contact with Xe. Remarkably, the Xe CS in the present, highly dynamic and conformationally flexible situations is found to depend linearly on the coordination number of the Xe atom. We interpret the high- and low-CS situations in terms of the magnetic absorption spectrum and choose our preference among the used MD methods based on comparison with the experimental CS. We check the role of spin-orbit coupling by comparing with fully relativistic CS calculations. The study outlines the computational workflow required to realistically model the CS of Xe confined in dynamic cavity structures under experimental conditions, and contributes to microscopic understanding of XBSs.

Energetics and exchange of xenon and water in a prototypic cryptophane-A biosensor structure.

A microscopic description of the energetics and dynamics of xenon NMR biosensors can be experimentally difficult to achieve. We conduct molecular dynamics and metadynamics simulations of a prototypical Xe@cryptophane-A biosensor in an explicit water solvent. We compute the non-covalent Xe binding energy, identify the complexation mechanism of Xe, and calculate the exchange dynamics of water molecules between the solution and the host. Three distinct, hitherto unreported Xe exchange processes are identified, and water molecules initialize each one. The obtained binding energies support the existing literature. The residence times and energetics of water guests are reported. An empty host does not remain empty, but is occupied by water. The results contribute to the understanding and development of Xe biosensors based on cryptophane derivatives and alternative host structures.